Method for preparing Febuxostat through one-pot process

A technology of febuxostat and compounds, which is applied in the field of improvement of febuxostat preparation, can solve the problems of difficult separation and recovery of formic acid, inconvenient concentration and recovery, pollution of three wastes, etc., achieve short operation time, save labor costs and equipment costs, Easy to handle effects

Inactive Publication Date: 2016-12-07
ZHEJIANG HUAHAI PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The disadvantages of the above preparation methods are: 1) formic acid has a pungent smell, and the aftertreatment method reported in the prior art is to add water to the reaction mixture, but formic acid is miscible with water, and formic acid is difficult to separate and reclaim, and there is a large amount of Three wastes pollution; 2) prior art all uses higher boiling point DMF to make reaction solvent, and this solvent itself is more expensive, and is miscible with water, and aftertreatment is also difficult to reclaim, causes environmental pollution, is also not easy to concentrate and recycle

Method used

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  • Method for preparing Febuxostat through one-pot process
  • Method for preparing Febuxostat through one-pot process
  • Method for preparing Febuxostat through one-pot process

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the preparation of compound I

[0038] In a 1L four-necked bottle, put 60g of febuxostat aldehyde, 866.7g of anhydrous formic acid, 17.3g of hydroxylamine hydrochloride and 24g of anhydrous sodium acetate, and stir to raise the temperature. At T=100~105°C, keep stirring for 10h, and distill the feed liquid under reduced pressure until there is no fraction to obtain a powdery solid [purity (HPLC): 98.8%, single impurity (HPLC): 0.36%, total impurity (HPLC): 1.2 %]; reclaim formic acid 782.1g, recovery rate 90.2%. Throw in 360 mL of ethyl acetate, 116 g of potassium carbonate, 3 g of KI and stir to raise the temperature. At T=65° C., start to drop 116.5 g of bromoisobutane solution. After dropping, t=70°C, keep warm for 5h, cool down the feed solution, t=15°C, stir for 30min, filter, add 120mL of water and beat for 1.5h, filter to obtain the wet product of Compound IV. Purity (HPLC): 98.9%, single impurity (HPLC): 0.15%, total impurity (HPLC): 1.1%, wherei...

Embodiment 2

[0044] Embodiment 2: the preparation of compound I

[0045]In a 1L four-necked bottle, put 60g of febuxostat aldehyde, 866.7g of anhydrous formic acid, 17.3g of hydroxylamine hydrochloride and 24g of anhydrous sodium acetate, and stir to raise the temperature. At T=100-105°C, heat-preserve and stir for 10 hours, distill the feed liquid under reduced pressure until there is no distillate to obtain a powdery solid. Purity (HPLC): 97.9%, single impurity (HPLC): 0.43%, total impurity (HPLC): 2.1%.

[0046] The resulting solid was put into 360 mL of ethyl acetate, 47.1 g of potassium hydroxide, 3 g of KI and stirred to raise the temperature. At T=65°C, 116.5 g of isobutane bromide solution was started to be added dropwise. After dropping, t=70°C, keep warm for 5h, cool down the feed solution, t=15°C, stir for 30min, filter, add 120mL of water and beat for 1.5h, filter to obtain the wet product of compound IV. Purity (HPLC): 94.6%, single impurity (HPLC): 3.7%, total impurity (HP...

Embodiment 3

[0048] Embodiment 3: the preparation of compound I

[0049] In a 1L four-necked bottle, put 60g of febuxostat aldehyde, 866.7g of anhydrous formic acid, 17.3g of hydroxylamine hydrochloride and 24g of anhydrous sodium acetate, and stir to raise the temperature. At T=100-105°C, heat-preserve and stir for 10 hours, distill the feed liquid under reduced pressure until there is no distillate to obtain powdery solid compound Ш. Weighing 86.8g, molar yield 97.6%, purity (HPLC): 98.9%, single hetero (HPLC): 0.22%, total hetero (HPLC): 1.1%.

[0050] Take 21.0 g of the obtained solid compound, put into 105 mL of ethyl acetate, 29.0 g of potassium carbonate, 1.0 g of KI and stir to raise the temperature. At T=65°C, 116.5 g of isobutane bromide solution was started to be added dropwise. After dropping, t=70°C, keep warm for 5h, cool down the feed solution, t=15°C, stir for 30min, filter, add 120mL of water and beat for 1.5h, filter to obtain the wet product of compound IV. Dry to obt...

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Abstract

The invention provides a method for preparing Febuxostat through a one-pot process. The method comprises the following steps: (1) preparing a compound III from a compound II, after a reaction is completed, carrying out direct concentrating and drying, and directly carrying out a subsequent reaction without treatment; (2) under the condition of the presence of an acid binding agent, allowing the compound III to react with bromo isobutane in an organic solvent so as to obtain a suspension of a compound IV, then carrying out filtering, subjecting a filter cake to pulping with water, and carrying out filtering so as to obtain a solid compound IV; and (3) subjecting the solid compound IV prepared in the step (2) to hydrolyzing so as to obtain a Febuxostat compound I, wherein a specific reaction formula is described in the specification.

Description

technical field [0001] The invention relates to an improved method for preparing febuxostat. Background technique [0002] The chemical name of febuxostat is 2-(3-cyano-isobutoxyphenyl)-4-methylthiazole-5-carboxylic acid, and its structural formula is as follows: [0003] [0004] Febuxostat is a xanthine oxidase (XO) inhibitor, suitable for the long-term treatment of hyperuricemia with gout symptoms. [0005] At present, there are many reports and patents on febuxostat, among which the prior art JP 2834971, WO2012014117, WO 2012066561, CN103304512A, CN101412699 and IN 2010MU02281 all report the following preparation methods, and the synthesis routes are as follows: [0006] [0007] This route takes 2-(4-hydroxyphenyl)-4-methylthiazole-5-carboxylic acid ethyl ester as raw material, and prepares 2-(3-formyl-4-hydroxyphenyl)- 4-Methylthiazole-5-carboxylic acid ethyl ester, followed by cyanation, isobutyl, hydrolysis and acidification in turn to generate febuxostat. A...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): C07D277/56A61K31/426A61P19/06
CPCA61K31/426C07D277/56
Inventor王青松金从阳张文灵王鹏
OwnerZHEJIANG HUAHAI PHARMACEUTICAL CO LTD